American Academy of Pediatrics Committee on Infectious Diseases and
Committee on Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for
the use of palivizumab and update on the use of RSV-IVIG. Pediatrics.1998;102:1211-1216.

US Department of Health and Human Services. Detailed Data 1979-96: Public Use Data Tape Documentation:
Natality. Hyattsville, Md: Centers for Disease Control and Prevention, National
Center for Health Statistics; 1998.

Bronchiolitis-Associated Hospitalizations Among US Children, 1980-1996

Author Affiliations: Respiratory and Enteric Viruses Branch (Drs Shay and Anderson) and Office of the Director (Mr Holman), Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga; Division of General Pediatrics, Department of Pediatrics, University of Washington School of Medicine, Seattle (Drs Newman, Liu, and Stout); and Department of Health Services, University of Washington School of Public Health and Community Medicine, Seattle (Dr Stout).

Context Respiratory syncytial virus (RSV) causes more lower respiratory tract
infections, often manifested as bronchiolitis, among young children than any
other pathogen. Few national estimates exist of the hospitalizations attributable
to RSV, and recent advances in prophylaxis warrant an update of these estimates.

Objectives To describe rates of bronchiolitis-associated hospitalizations and to
estimate current hospitalizations associated with RSV infection.

Design and Setting Descriptive analysis of US National Hospital Discharge Survey data from
1980 through 1996.

Participants Children younger than 5 years who were hospitalized in short-stay, nonfederal
hospitals for bronchiolitis.

Main Outcome Measure Bronchiolitis-associated hospitalization rates by age and year.

Results During the 17-year study period, an estimated 1.65 million hospitalizations
for bronchiolitis occurred among children younger than 5 years, accounting
for 7.0 million inpatient days. Fifty-seven percent of these hospitalizations
occurred among children younger than 6 months and 81% among those younger
than 1 year. Among children younger than 1 year, annual bronchiolitis hospitalization
rates increased 2.4-fold, from 12.9 per 1000 in 1980 to 31.2 per 1000 in 1996.
During 1988-1996, infant hospitalization rates for bronchiolitis increased
significantly (P for trend <.001), while hospitalization
rates for lower respiratory tract diseases excluding bronchiolitis did not
vary significantly (P for trend = .20). The proportion
of hospitalizations for lower respiratory tract illnesses among children younger
than 1 year associated with bronchiolitis increased from 22.2% in 1980 to
47.4% in 1996; among total hospitalizations, this proportion increased from
5.4% to 16.4%. Averaging bronchiolitis hospitalizations during 1994-1996 and
assuming that RSV was the etiologic agent in 50% to 80% of November through
April hospitalizations, an estimated 51,240 to 81,985 annual bronchiolitis
hospitalizations among children younger than 1 year were related to RSV infection.

Conclusions During 1980-1996, rates of hospitalization of infants with bronchiolitis
increased substantially, as did the proportion of total and lower respiratory
tract hospitalizations associated with bronchiolitis. Annual bronchiolitis
hospitalizations associated with RSV infection among infants may be greater
than previous estimates for RSV bronchiolitis and pneumonia hospitalizations
combined.

Respiratory syncytial virus (RSV) is the most important cause of lower
respiratory tract disease among infants and children worldwide.1,2
Almost all children have been infected with RSV by age 2 years.3
Although reinfection throughout life is common, a child's initial RSV infection
typically is the most severe and the most likely to involve the lower respiratory
tract.3,4 Severe RSV disease,
as gauged by the requirement for hospital admission, is most common among
infants aged 1 to 3 months.3,5

The hallmark of RSV infection is bronchiolitis, a disease of infancy
characterized by wheezing, lung hyperexpansion, and hypoxia. Other lower respiratory
tract illnesses, especially pneumonia, are also common manifestations of RSV
infection. In studies of hospitalized children in temperate countries, RSV
infection has been associated with 43% to 74% of bronchiolitis cases6- 12
and with 19% to 54% of pneumonia cases.6- 10
During the 1985-1994 winter seasons in Rochester, NY, RSV was associated with
50% to 80% of bronchiolitis hospitalizations and with 30% to 60% of pneumonia
hospitalizations.13

The only national estimates of hospitalizations attributable to RSV
infection were made by the Institute of Medicine in 1985.14
By estimating that 0.5% of children younger than 5 years infected with RSV
would require hospitalization, and assuming that 60% of RSV-associated hospitalizations
would occur among infants younger than 1 year, the Institute of Medicine projected
that 54,697 infants younger than 1 year and 36,465 children aged 1 through
4 years were hospitalized annually for bronchiolitis or pneumonia associated
with RSV.

Recent progress in 2 areas warrants updating national RSV-associated
hospitalization estimates. First, the Food and Drug Administration recently
licensed palivizumab, a humanized murine RSV monoclonal antibody for monthly
intramuscular administration among high-risk children during RSV seasons to
prevent lower respiratory tract disease hospitalizations.15
Palivizumab is easier to deliver and less expensive than the previously available
prophylactic antibody preparation, RSV-enriched human immunoglobulin, which
must be intravenously administered. Recommendations from the American Academy
of Pediatrics regarding use of both products among high-risk infants are available.16 Second, advances in the development of safe subunit
and live attenuated RSV vaccine candidates have been reported recently.17- 19 To update hospitalization
estimates, we examined temporal trends in hospitalizations among US children
associated with bronchiolitis, the most specific RSV-associated illness. We
estimated recent RSV-associated hospitalizations by using discharge data for
bronchiolitis and used bronchiolitis and pneumonia hospitalizations to estimate
RSV-associated morbidity among infants.

Methods

Hospital discharge data from 1980 through 1996 were obtained from the
National Hospital Discharge Survey (NHDS) through the National Center for
Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC).20 The NHDS is a representative sample of patient discharge
records from short-stay, nonfederal, general and children's hospitals in the
United States.21 Hospitalizations were weighted
using NCHS procedures to obtain national estimates.22
NHDS records do not contain individual identifiers; therefore, the unit of
analysis was a hospitalization.

All discharge records from children younger than 5 years with an International Classification of Diseases, Ninth Revision, Clinical
Modification (ICD-9-CM) code for any respiratory
illness (codes 460-519)23 among the as many
as 7 discharge diagnoses listed were selected for study. A bronchiolitis-associated
hospitalization was defined as a discharge with acute bronchiolitis (code
466.1) listed anywhere on the record. Use of this strategy detected hospitalizations
for which a bronchiolitis-associated complication (eg, respiratory failure)
might be coded first and those associated with nosocomially acquired bronchiolitis,
which may represent a substantial proportion of RSV-associated bronchiolitis
among hospitalized infants.24,25
Severe bronchiolitis was defined as a discharge listing an ICD-9-CM procedure code for endotracheal intubation (code 96.04) or
for receipt of continuous mechanical ventilation (codes 96.72 or 96.71 [1992-1996];
93.92 [1988-1991]; or 93.90 [1980-1987]).23

Hospitalizations were stratified by patient age: younger than 6 months,
6 through 11 months, 12 through 23 months, or 24 through 59 months. For approximately
1.0% of bronchiolitis hospitalizations, age data were missing; these records
were not included in analyses. Hospitalizations were also stratified by sex,
length of stay, and census geographic region (Northeast, Midwest, South, and
West).26 Because data on race/ethnicity were
missing from 23% of discharge records examined, we made no comparisons by
ethnicity.21,27 Temporal trends
in hospitalizations were examined by discharge month and year. From 1988 through
1996, aggregate estimates of discharges by month were made using only records
sampled from hospitals fully responding for that year (I. M. Shimizu, PhD,
NCHS, written communication, November 16, 1998).20
Bronchiolitis and pneumonia hospitalizations attributable to RSV were estimated
using winter RSV recovery rates among children hospitalized with bronchiolitis
(50% to 80%) or pneumonia (30% to 60%).6- 13
Only hospitalizations occurring from November through April were used in estimating
disease likely attributable to RSV infection.

Hospitalization rates were calculated using denominators derived from
US census data for children younger than 5 years23
or from US natality data for children younger than 1 year.28
Population estimates of children age 1 through 4 years for each calendar year
were made by subtracting natality figures from census figures. Rates were
expressed as the number of estimated hospitalizations per 1000 children of
the corresponding age group.

The NHDS was redesigned in 1988, when new methods of sampling hospitals
and collecting data were introduced; however, most estimates obtained using
the old and the new methods have not been substantially different.29 SUDAAN software30
was used to calculate annual SEs during 1988-1996 to account for the stratified
sampling techniques used during this period.29
Overall SEs for the entire study period were estimated using NCHS procedures.20,28 Denominators obtained from vital
records data were considered free from sampling error.26,28
Statistical tests for rate comparisons were performed only with 1988-1996
hospitalization data because of the 1988 changes in survey design. Comparisons
were made by period and demographic characteristics with 2-sided t tests incorporating weighted variance estimates.30,31
A weighted least squares regression method was used as a test for trend with
data obtained from 1988 through 1996.22

Results

Bronchiolitis Hospitalizations

From 1980 through 1996, an estimated 1,648,281 (SE, 121,129) hospitalizations
associated with bronchiolitis occurred among US children younger than 5 years.
Eighty-one percent (1,334,566; SE, 105,396) of these hospitalizations occurred
among children younger than 1 year and 57% (946,358; SE, 83,309) among children
younger than 6 months. As expected for an illness frequently associated with
RSV infection, bronchiolitis hospitalizations peaked annually during the winter
months, usually in January or February (Figure
1). Among children younger than 5 years, 81% of bronchiolitis hospitalizations
occurred from November through April, and among children younger than 1 year,
83% occurred during these months.

During the study period, we estimated that bronchiolitis hospitalizations
accounted for 7.0 million inpatient days (SE, 575,554). The median length
of stay was 3 days per hospitalization (interquartile range, 2-5 days). Length
of stay did not vary substantially by age in months, by sex, or by calendar
year (data not shown).

Although the annual number of bronchiolitis hospitalizations fluctuated,
they increased among children in each age group during the study period (Figure 2). The most dramatic rise in hospitalizations
occurred among children younger than 6 months, for whom bronchiolitis hospitalizations
increased by 239% from 1980 to 1996.

Among children aged 1 through 4 years, the bronchiolitis hospitalization
rate increased gradually, from 1.3 per 1000 in 1980 to 2.3 per 1000 in 1996
(+77%). Among children younger than 1 year, rates increased more rapidly during
this period, from 12.9 per 1000 to 31.2 per 1000 (+152%).

Bronchiolitis hospitalization rates increased proportionately among
males and females. Among infant males, the rate increased from 24.9 per 1000
during 1988-1990 to 38.4 per 1000 during 1994-1996 (+54%; P = .01); among infant females the rate increased from 15.1 to 24.4
per 1000 (+62%; P = .02) during these periods. Males
were 1.6 times more likely to be hospitalized with bronchiolitis than females,
irrespective of age group or calendar year.

Bronchiolitis hospitalization rates among infants increased in each
of the 4 regions of the United States. However, the only statistically significant
increase took place in the South, where the annual average hospitalization
rate increased from 19.0 per 1000 in 1988-1990 to 33.4 per 1000 in 1993-1995
(+75.8%; P = .03).

Hospitalization Rates for Lower Respiratory Tract Diseases

From 1980 through 1996, bronchiolitis was responsible for increasing
proportions of lower respiratory tract disease and total hospitalizations
among children younger than 1 year. The proportion of total hospitalizations
among children younger than 1 year associated with bronchiolitis increased
from 5.4% to 16.4%; for lower respiratory tract diseases, the proportion diagnosed
with bronchiolitis increased from 22.2% to 47.4% (Table 1).

To determine whether bronchiolitis hospitalization rates were influenced
by temporal trends in diagnostic coding practices, we examined hospitalization
rates for other lower respiratory tract diseases. Hospitalization rates among
children younger than 1 year for all lower respiratory diseases increased
by 13% during the study period, from 58.1 per 1000 in 1980 to 65.8 per 1000
in 1996 (Figure 3). Pneumonia hospitalization
rates declined from 28.5 per 1000 in 1980 to 23.9 per 1000 in 1988, while
bronchiolitis hospitalization rates increased from 12.9 to 17.3 per 1000.
The increase in bronchiolitis rates during 1980-1988 may have resulted, in
part, from a trend to diagnose bronchiolitis instead of pneumonia among children
younger than 1 year. However, bronchiolitis hospitalization rate increases
after 1989 among children younger than 1 year were not accompanied by concomitant
rate decreases for either pneumonia or asthma (Figure 3). Finally, hospitalization rates for bronchiolitis and
all lower respiratory tract diseases increased significantly during 1988-1996
(P for trend <.001 for each comparison), while
hospitalization rates for all lower respiratory tract diseases except for
bronchiolitis did not vary significantly (P for trend
= .20).

Recent Patterns in Bronchiolitis Hospitalizations

Specific diagnoses and procedures associated with bronchiolitis discharges
were examined in detail during 1994-1996 to determine the most recent hospitalization
patterns. Bronchiolitis was the first-listed diagnosis in 83% of records.
Pneumonia, organism unspecified (4.5%), RSV pneumonia (2.9%), asthma (1.9%),
and bronchopneumonia (1.1%) were other common first-listed diagnoses. The
most frequent underlying conditions recorded for bronchiolitis-associated
discharges were congenital heart disease (2.4%), chronic respiratory distress
arising in the perinatal period (2.0%), and a history of perinatal problems
(1.4%).

Severe bronchiolitis was uncommon during the entire study period, but
it may have become more prevalent in recent years. Among children younger
than 1 year during the entire study, 1.0% of bronchiolitis hospitalizations
were coded for endotracheal intubation or receipt of continuous mechanical
ventilation. However, during 1994-1996, the discharges of 1.7% of children
younger than 1 year hospitalized with bronchiolitis were coded for endotracheal
intubation or for receipt of continuous mechanical ventilation.

Procedures frequently coded for the discharges of children younger than
1 year with a 1994-1996 bronchiolitis-associated hospitalization included
nebulization therapy (17.2%), receipt of supplemental oxygen (8.6%), lumbar
puncture (4.8%), and antibiotic injection (1.3%).

Estimates of RSV-Associated Hospitalizations

To provide current estimates of RSV-associated morbidity, we averaged
bronchiolitis hospitalizations among children younger than 1 year and 5 years
during 1994-1996. An average of 123,471 bronchiolitis hospitalizations occurred
annually among children younger than 1 year and 154,365 among children younger
than 5 years during this 3-year period. Assuming that 50% to 80% of bronchiolitis
hospitalizations occurring during November through April were attributable
to RSV, we estimated that 51,240 to 81,985 children younger than 1 year and
62,518 to 100,029 children younger than 5 years were hospitalized during each
of these years for RSV-associated bronchiolitis.

We also estimated the contribution of RSV to pneumonia hospitalizations
among children younger than 1 year. Assuming that 30% to 60% of November through
April pneumonia hospitalizations in 1994-1996 were RSV-related, 22,160 to
44,321 infant pneumonia hospitalizations annually were attributable to RSV
infection.

Comment

Our study is the first to examine temporal trends in bronchiolitis hospitalizations
and estimate RSV-associated hospitalizations by using nationally representative
data. Our finding that bronchiolitis hospitalizations have increased substantially
during the 17 years studied was not expected. We found that infant bronchiolitis
hospitalization rates increased significantly from 1988 through 1996, while
hospitalization rates for other lower respiratory tract diseases did not vary
significantly. Among infants, bronchiolitis currently is associated with approximately
47% of lower respiratory tract disease discharges and with 16% of total discharges.

In 1985, the Institute of Medicine estimated that 91,162 hospitalizations
for bronchiolitis and pneumonia associated with RSV occurred annually among
US children younger than 5 years.14 For bronchiolitis
alone, we estimate that 62,500 to 100,000 RSV-associated hospitalizations
occur annually among children younger than 5 years. The Institute of Medicine
appeared to underestimate the RSV-associated disease burden among infants
younger than 1 year because they assumed that 60% of RSV hospitalizations
among children younger than 5 years would occur among infants. We found that
81% of bronchiolitis hospitalizations occurred among infants. Our estimate
of 51,200 to 82,000 annual infant hospitalizations for RSV-associated bronchiolitis
is similar in magnitude to the 1985 Institute of Medicine projection of 54,700
RSV-associated infant hospitalizations for bronchiolitis and pneumonia combined.14 Currently, we estimate that 73,400 to 126,300 annual
hospitalizations among US infants for bronchiolitis or pneumonia may be attributable
to RSV infection, considerably more than the 1985 projection.

The etiology of the increase in bronchiolitis hospitalization rates
is probably multifactorial. Trends in child-care practices, changes in the
criteria for hospitalization of children with lower respiratory tract disease,
decreasing mortality among premature and medically complex infants at high
risk for RSV-associated hospitalization, changes in RSV strain virulence,
modifications in the NHDS, or alterations in diagnostic coding practices during
the study period are potential reasons for the increases.

Several of these factors are unlikely to contribute substantially to
increasing bronchiolitis hospitalization rates. Although RSV strains vary
in virulence,32- 34
and strain differences may account for variation in the severity of RSV outbreaks,
documented RSV strain circulation patterns do not suggest that increasing
strain virulence is responsible for the national temporal trends we found.35 A predominant national RSV outbreak strain or strains
have not been documented. Instead, the pattern of outbreak strains vary by
community each year.36,37 Similarly,
although modification of NHDS procedures in 1988 could affect the comparability
of discharge data collected before and after that year, much of the increase
in bronchiolitis hospitalization rates has taken place since 1989 and cannot
be explained by design changes. Finally, if diagnostic-coding variations during
the study period substantially influenced the increase in bronchiolitis hospitalization
rates, we would expect a compensatory decrease in hospitalization rates for
other lower respiratory tract diseases with clinical presentations similar
to bronchiolitis. From 1988 through 1996, when infant bronchiolitis hospitalization
rates almost doubled, hospitalization rates for unspecified pneumonia and
asthma also increased. Therefore, it is difficult to postulate that diagnostic
substitution fully explains the increase in bronchiolitis hospitalization
rates.

Other factors may have contributed to increases in bronchiolitis hospitalization
rates. Attendance at a child-care center with 6 or more other children is
an independent risk factor for a lower respiratory tract disease hospitalization
in the first 2 years of life.38 Enrollment
of children younger than 3 years in center-based child care increased during
the study. Among children aged 1 through 2 years with employed mothers, the
proportion enrolled in child-care centers increased from 12% in 1982 to 25%
in 1993. Among children younger than 1 year, enrollment increased from 5%
to 20%.39 A trend toward earlier enrollment
in large child-care centers may lead to initial RSV infection at a younger
age, when hospitalization is more likely. Specific child-care practices must
be examined in relation to bronchiolitis hospitalization trends.

Criteria for hospital admission among children with bronchiolitis may
have changed during the study period and influenced hospitalization rates.
Specifically, pulse oximetry measurements during the evaluation of wheezing
children became more common and may have led to new criteria for hospital
admission. In a prospective study of wheezing children presenting to a pediatric
emergency department, the proportion receiving pulse oximetry increased from
87% during December 1987 through May 1988 to 96% during June through September
1991. The corresponding hospitalization rate among wheezing children increased
from 10.4% to 15.6%.40 A study examining routine
pulse oximetry use during emergency department evaluation of children with
respiratory symptoms found that oximetry detected an oxygen saturation of
less than 92% more effectively than physical examination alone.41
If mild-to-moderate hypoxia detected by pulse oximetry has been added to traditional
criteria for hospitalizing young children with bronchiolitis (eg, respiratory
distress or difficulty feeding), then increasing use of pulse oximetry may
explain the increase in hospitalization rates. Although we are unaware of
any data specifically examining oximetry use trends in children with bronchiolitis,
a national survey of 376 emergency departments in 1992 found that 67% routinely
used pulse oximetry in the assessment of pediatric asthma.42

Improved survival of prematurely born infants at greater risk for serious
RSV-associated disease may have influenced bronchiolitis hospitalization rates.
Nevertheless, our data suggest that such high-risk infants represent a small
proportion of children hospitalized with bronchiolitis: only 2% of 1994-1996
bronchiolitis discharges were concurrently coded for chronic lung disease.
It is possible that underlying medical conditions were underreported in NHDS
data. Procedures were underreported in these data. While approximately 9%
of bronchiolitis discharge records during 1994-1996 were coded for receipt
of supplemental oxygen, hospital-based studies have reported that 34% to 75%
of RSV-infected children received supplemental oxygen.43- 45
Underreporting of procedures may reflect a lack of reimbursement for routine
hospital care such as oxygen administration. The possible contribution of
underlying conditions, including premature birth and congenital heart disease,
to bronchiolitis hospitalization trends needs to be more fully ascertained.
However, it is unlikely the survival of more premature infants could account
for a substantial proportion of the increase in infant bronchiolitis hospitalization
rates.

This study has several limitations. First, NHDS-based hospitalization
estimates are generated by using a complex, nationally representative sample
of discharges, which in 1996 were amassed from 480 responding hospitals.21 Thus, the weighted estimates have more variability
than might be expected from the magnitude of the numbers presented. We have
presented SEs where appropriate so that this variability can be assessed.
Second, the NHDS does not include hospitalizations occurring in federal facilities
providing pediatric care, particularly Indian Health Service hospitals—and
the highest US hospitalization rate for RSV disease ever reported was among
Alaska Native infants in the southwestern part of the state (100/1000).46 Third, data that may relate to socioeconomic status,
such as race/ethnicity and insurance coverage, are incompletely recorded in
NHDS records, precluding examination of these factors. Infants born to low-income
urban families have increased admission rates for acute lower respiratory
tract disease compared with those born to middle-income families.3,47- 51
Socioeconomic factors need to be examined in relation to temporal trends in
bronchiolitis hospitalizations. Finally, lack of a specific ICD-9-CM code for RSV-associated disease forced us to use a proportion
of bronchiolitis hospitalizations occurring from November through April as
the primary proxy for RSV-associated hospitalizations. We believe this approach
is reasonable. Many studies have documented that RSV is responsible for the
majority of winter bronchiolitis hospitalizations,6- 13
and annual RSV detections in the National Respiratory and Enteric Virus Surveillance
System correlate closely with annual peaks of bronchiolitis hospitalizations
in NHDS data (CDC unpublished data, 1990-1996).52,53
In those years with a particularly prominent mid-winter peak in bronchiolitis
hospitalizations, it is likely that a greater proportion of bronchiolitis
hospitalizations are associated with RSV infection; however, we were not able
to document this possibility, as no virologic data were abstracted for NHDS
records.

In summary, nationally representative data suggest that the current
number of RSV-associated bronchiolitis and pneumonia hospitalizations among
infants is approximately 1.5 to 2 times greater than previously estimated.
From 1980 through 1996, bronchiolitis hospitalization rates and the proportion
of hospitalizations associated with bronchiolitis increased substantially
among infants. Finally, despite the availability of prophylactic antibody
preparations to reduce RSV-associated hospitalizations among children with
conditions placing them at high risk for serious disease,15,16
the majority of US infants hospitalized with bronchiolitis are not concurrently
diagnosed with prematurity or underlying lung disease. A safe and effective
RSV vaccine is needed to reduce bronchiolitis hospitalizations.

American Academy of Pediatrics Committee on Infectious Diseases and
Committee on Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for
the use of palivizumab and update on the use of RSV-IVIG. Pediatrics.1998;102:1211-1216.

US Department of Health and Human Services. Detailed Data 1979-96: Public Use Data Tape Documentation:
Natality. Hyattsville, Md: Centers for Disease Control and Prevention, National
Center for Health Statistics; 1998.